Grant: RFA- DK-08-001 Title: Functionalized, Nanoscale Coatings for Islet Encapsulation PI: Cherie Stabler Project Summary While clinical islet transplantation (CIT) has shown promise for the treatment of Type 1 diabetes, it is dampened by the impaired function and loss of islets following implantation. This loss is attributed to strong inflammatory and immunological response to the transplant, primarily due to cell surface inflammatory proteins and antigens. In this proposal, we seek to minimize detrimental host responses that lead to islet engraftment failure by encapsulating the islets in novel nanoscale biomaterial layers. By developing stable capsules on the order of 1000-fold smaller than standard practices via controlled covalent linking of individual polymers layers on the islet surface, void volumes are dramatically reduced and nutritional transport and glucose sensing is unaffected. Nanoscale layers not only serve as a means to immunocamouflage the implant, but also have tremendous potential to optimize the composition, structure, thickness, and function of these layers on the nanometer level. Once fabricated, these nanoscale layers serve as ideal platforms for the tethering of functional agents, proteins or markers capable of dynamically interacting at the implant-host interface. Therefore, the inert biomaterial layer can be converted to a bioactive surface capable of actively altering the localized implant environment. In this proposal, we seek to tether active immunomodulatory proteins/enzymes, anti-inflammatory agents, and/or engraftment- enhancing nanoparticles to the nanolayer surface. The design of effective strategies to build tailored nano-layers on the islet surface capable of expressing active pro- engraftment agents could significantly improve transplant efficacy and long-term stability. The public health implications of this research are that this approach may provide a means to dramatically improve current clinical islet transplantation results, by reducing or completely eliminating the need for immunosuppressive therapy and improving long- term implant function.